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Autoantigen-B Cell Antigen Receptor Interactions That Regulate Expression of B Cell Antigen Receptor Loci¹

Xiaohe Liu^*, Lawrence J. Wysocki and Tim Manser^2,*

^* Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107; and Integrated Department of Immunology, National Jewish Medical and Research Center, and University of Colorado Health Science Center, Denver, CO 80206

Levels of AgR (BCR) expression are regulated during B cell development, activation, and induction of tolerance. The mechanisms responsible for and consequences of this regulation are poorly understood. We have described a class of DNA-based autoantigen-reactive B cell that down-regulates BCR expression during development to mature follicular phenotype. In this study, we show that at immature stages of primary differentiation, individual B cells of this type can dynamically modulate levels of expression of BCR in inverse proportion to degree of autoantigen engagement and induced BCR signaling. These adjustments in BCR expression are not associated with cell death, BCR revision, or altered development, and do not require TLR 9. Strikingly, modulation of BCR subunit gene RNA levels and transcription parallels these changes in BCR expression, indicating a direct link between autoantigen-BCR interactions of this type and regulation of transcription of BCR-encoding loci. We propose that this adaptive process allows this class of autoreactive B cell to avoid conventional tolerance pathways and promotes development to mature phenotype.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health to T.M. (AI038965) and L.J.W. (AI033613 and AI048108).

² Address correspondence and reprint requests to Dr. Tim Manser, Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Room 469, Jefferson Alumni Hall, 1020 Locust Street, Philadelphia, PA 19107. E-mail address: manser{at}mail.jci.tju.edu

³ Abbreviations used in this paper: sIgM, surface IgM; GC, germinal center; Ars, arsonate; sIgD, surface IgD; FO, follicular; BM, bone marrow; HEL, hen egg lysozyme; MFI, mean fluorescence intensity; QPCR, quantitative PCR; HPRT, hypoxanthine phosphoribosyltransferase; MCD, methyl--cyclodextrin; PABA, para-aminobenzoic acid.

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				F. Coffey, X. Liu, and T. Manser Primary Development and Participation in a Foreign Antigen-Driven Immune Response of a Chromatin-Reactive B Cell Clonotype Are Not Influenced by TLR9 or Other MyD88-Dependent TLRs J. Immunol., November 15, 2007; 179(10): 6663 - 6672. [Abstract] [Full Text] [PDF]